MicroRNAs Mediate Dietary-Restriction-Induced Longevity through PHA-4/FOXA and SKN-1/Nrf Transcription Factors

BACKGROUND Dietary restriction (DR) has been shown to prolong longevity across diverse taxa, yet the mechanistic relationship between DR and longevity remains unclear. MicroRNAs (miRNAs) control aging-related functions such as metabolism and lifespan through regulation of genes in insulin signaling, mitochondrial respiration, and protein homeostasis. RESULTS We have conducted a network analysis of aging-associated miRNAs connected to transcription factors PHA-4/FOXA and SKN-1/Nrf, which are both necessary for DR-induced lifespan extension in Caenorhabditis elegans. Our network analysis has revealed extensive regulatory interactions between PHA-4, SKN-1, and miRNAs and points to two aging-associated miRNAs, miR-71 and miR-228, as key nodes of this network. We show that miR-71 and miR-228 are critical for the response to DR in C. elegans. DR induces the expression of miR-71 and miR-228, and the regulation of these miRNAs depends on PHA-4 and SKN-1. In turn, we show that PHA-4 and SKN-1 are negatively regulated by miR-228, whereas miR-71 represses PHA-4. CONCLUSIONS Based on our findings, we have discovered new links in an important pathway connecting DR to aging. By interacting with PHA-4 and SKN-1, miRNAs transduce the effect of dietary-restriction-mediated lifespan extension in C. elegans. Given the conservation of miRNAs, PHA-4, and SKN-1 across phylogeny, these interactions are likely to be conserved in more-complex species.